EP1126834A1 - Schema posologique analgesique - Google Patents

Schema posologique analgesique

Info

Publication number
EP1126834A1
EP1126834A1 EP99951876A EP99951876A EP1126834A1 EP 1126834 A1 EP1126834 A1 EP 1126834A1 EP 99951876 A EP99951876 A EP 99951876A EP 99951876 A EP99951876 A EP 99951876A EP 1126834 A1 EP1126834 A1 EP 1126834A1
Authority
EP
European Patent Office
Prior art keywords
tramadol
days
day
titration
regimen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99951876A
Other languages
German (de)
English (en)
Inventor
Marc Kamin
William Olson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Janssen Pharmaceuticals Inc
Original Assignee
Ortho McNeil Pharmaceutical Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ortho McNeil Pharmaceutical Inc filed Critical Ortho McNeil Pharmaceutical Inc
Publication of EP1126834A1 publication Critical patent/EP1126834A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • This invention relates to a dosing regimen for the administration of the analgesic tramadol.
  • the dosing regimen achieves the desired analgesic effect while reducing or delaying the on-set of the side effects generally associated with the administration of tramadol.
  • Tramadol the chemical name for which is 2- [ (dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol, is a synthetic, centrally-acting analgesic that is effective for the treatment of moderate to moderately- severe chronic pain. It has been marketed under the trade name TramalTM since 1977 in the dosage forms of capsules, injections, suppositories and drops.
  • the compound can be employed as the free base or its pharmaceutically acceptable salts, stereo isomers and solvates. It is generally supplied in the form of its hydrochloride salt and over 400 million doses of tramadol have been administered since its introduction in Germany.
  • analgesic therapeutic regimen that is both effective and well tolerated.
  • the two traditional categories of analgesics i.e. opioids and nonsteroidal anti- inflammatory drugs (NSAIDs)
  • opioids and nonsteroidal anti- inflammatory drugs are both effective but are associated with potentially serious side effects.
  • Concerns regarding tolerance and dependence minimize the chronic use of narcotics such as morphine and codeine for the treatment of chronic pain.
  • Patients on chronic NSAID therapy risk severe gastrointestinal symptoms, including ulceration and bleeding which have been estimated to result in up to 20,000 deaths each year.
  • An alternative to this dilemma is tramadol, a non-narcotic, non-NSAID analgesic which is indicated for the management of moderate to moderately-severe pain.
  • tramadol After oral administration, tramadol is rapidly and almost completely absorbed and is extensively metabolized. The major metabolic pathways appear to be N- and O- demethylation and glucuronidation or sulfation in the liver. Only one metabolite, i.e. mono-O- desmethyltramadol, has been found to be pharmacologically active .
  • peak plasma concentrations of tramadol hydrochloride occurring two hours after administration are 308+78 ng/ml mean+standard deviation) .
  • Peak plasma concentrations of mono-O-desmethyl tramadol, the active metabolite of tramadol are 55+20 ng/ml, occurring approximately three hours after administration.
  • the terminal plasma elimination half-lives of tramadol hydrochloride and its active metabolite are 6.3 ⁇ 11.4 hours and 7.4+1.4 hours respectively.
  • Tramadol is poorly bound to plasma proteins (20.2%) thus decreasing the potential for drug interactions with highly protein-bound agents.
  • tramadol is not completely understood, but in animal models at least two complementary mechanisms appear to be involved and they are 1) weak binding to the ⁇ opioid receptors and 2) weak inhibition of the reuptake of norepinephrine and serotonin.
  • Tramadol is not chemically related to opiates, but its actions are similar to those of opioid (narcotic) analgesics.
  • the opioid activity of tramadol results from the low-affinity binding of tramadol hydrochloride and the higher affinity binding of the metabolite to ⁇ receptors; however, its induced antinociception is only partially antagonized by the opiate antagonist naloxone in several animal tests.
  • the inhibition of norepinephrine and serotonin reuptake which has been demonstrated in vi tro, is postulated to contribute independently to the overall analgesic profile of tramadol hydrochloride.
  • Tramadol is well tolerated, however, nuisance adverse events such as drowsiness, vomiting and dizziness can occur during the initiation of treatment which may lead to early discontinuation of the treatment.
  • the most frequently reported adverse events observed in clinical trials of tramadol hydrochloride are constipation, nausea, dizziness/vertigo, headache, somnolence, and vomiting.
  • the efficacy, safety, and pharmacokinetic profile of tramadol hydrochloride indicate that the drug may be useful in treating chronic pain.
  • An object of the present invention is to demonstrate that the frequency of nausea and vomiting, two of the most frequently reported adverse events and the events most commonly associated with discontinuation of treatment, as well other adverse events, can be reduced using a lower dosage titration scheme without diminishing the efficacy of the compound.
  • the present invention relates to a dosage regimen which consists of slowing the titration rate for tramadol which results in a reduction of the incidence of discontinuation due to side effects such as nausea and vomiting.
  • the present invention relates to a dosage regimen for tramadol which involves a slower titration rate than that currently prescribed.
  • the slower rate of titration of tramadol therapy results in improved tolerability of the drug.
  • the novel regimen results in a significant reduction in discontinuations due to a lower incidence or severity of side effects.
  • tramadol is intended to include its pharmaceutically acceptable salts, stereo isomers and solvates thereof.
  • Tramadol is indicated for the treatment of moderate to moderately-severe pain and its typical dosing regimen is 50-100 mg every 4 to 6 hours. About 200 mg/day is considered to be a normal initial dose. Clinical studies have shown tramadol to be an effective treatment for chronic joint pain. Tramadol is well tolerated, however, nuisance adverse events can occur during initiation of treatment with tramadol. These side effects may lead to early discontinuation of tramadol therapy.
  • Slow titration of a therapeutic agent is often used by practicing clinicians to minimize adverse events associated with centrally-acting agents such as antidepressants, analgesics and anticonvulsants. Although slow titration may minimize the adverse side effects associated with a particular agent, it may also delay the onset of the effect of the agent as well. It has now been discovered that initiating tramadol therapy using slow titration rates according to the regimen of this invention minimizes discontinuations due to adverse side effects associated with tramadol while maintaining its therapeutic effectiveness which results in a greater tolerance of the drug during therapy.
  • the regimen which is the basis of the present invention is a 1-28 day regimen.
  • tramadol is administered over a ten-28 day period starting on day one in a pharmaceutical composition containing from about 10 - 50 mg of tramadol and the amount of drug is increased incrementally over the next 9-28 days until the target dose of about 200-400 mg/day is reached.
  • Many patients find effective pain relief at 200 mg/day, however, some patients may require doses of up to 400 mg/day in order to achieve the desired relief.
  • tramadol in the form of the free base or its pharmaceutically acceptable salt, is administered at a dose of about 10-50 mg .
  • tramadol On days 4-6 of the regimen tramadol is administered at a dose in the range of about 20-100 mg. On days 7-9 tramadol is administered at a dose in the range of about 30-150 mg and on days 10-28 and thereafter at a dose of about 40-400 mg. At the end of the period the therapy is continued at the target dose which may be anywhere from 200 to about 400 mg of tramadol.
  • tramadol is administered in a regimen which comprises administering tramadol at the rate of about 25 mg of tramadol on days 1-3; 50 mg of tramadol on days 4-6; 75 mg of tramadol on days 7-9; 100 mg of tramadol on days 10-12; 150 mg of tramadol on days 13-15; and 200 mg of tramadol on days 16-28 and thereafter.
  • tramadol is administered in a regimen which comprises administering tramadol at the rate of 50 mg of tramadol on days 1-3; 100 mg of tramadol on days 4-6; 150 mg of tramadol on days 7-9; and 200 mg of tramadol on day 10 and thereafter.
  • the drug is generally administered in the form of its pharmaceutically salt.
  • suitable pharmaceutically acceptable salts include salts of inorganic acids such as hydrochloric and hydrobromic acid.
  • the preferred salt is the hydrochloride salt .
  • the slower initial titration rate of tramadol is effective in reducing discontinuations due to adverse effects while maintaining the analgesic properties of the compound. This is particularly true in the case of patients who previously had difficulty tolerating an analgesic because of side effects such as nausea and/or vomiting. This result is based on the cumulative proportion of patients who discontinued use of the agent due to adverse side effects.
  • EXAMPLE 1 Tramadol, in the form of its hydrochloride salt, was studied in a multicenter, outpatient, randomized, double- blind parallel study that compared the effect of different titration rates of tramadol versus placebo on the incidence of discontinuations resulting from adverse events in patients with chronic joint pain.
  • a total of 465 patients with chronic joint pain were enrolled in the study and randomized into one of four treatment groups for 14 days. Patients continued on their prestudy dose of NSAIDs while concurrently receiving tramadol or placebo. Tramadol groups were titrated at three different rates to achieve the study target dose of 200 mg/day. Each group was examined to determine if a slower titration resulted in a statistically significant (p ⁇ 0.05) trend towards fewer discontinuations due to nausea and/or vomiting and dizziness and/or vertigo. Discontinuation due to any adverse event was similarly analyzed. If the trend was statistically significant, pairwise comparisons were performed to determine the statistical significance between titration rates.
  • the study protocol was approved by an Institutional Review Board at each study site and informed consent regarding the risks and benefits of participation was obtained for all patients.
  • Double-blind therapy began on Day 1, with patients receiving either placebo or one of three titration regimens, ultimately reaching the study target dose of 200 mg/day of tramadol in either 1 day, 4 days (increasing by 50 mg increments each day; Figures la, lb and lc) , or 10 days (increasing by 50 mg increments every 3 days) Patients continued to take their stable dose of NSAID throughout the double- blind phase, in addition to the study drug or placebo. On Day 14, all patients underwent a physical examination with clinical laboratory tests, as well as adverse event assessment Patients could be discontinued from the study as the result of adverse events, treatment failure, significant protocol violation, development of an intercurrent illness or at their own request.
  • Tramadol in the form of its hydrochloride salt, was studied in a multicenter, outpatient, randomized, double-blind parallel study comprised of two phases: a screening/open-label run-in study and a double-blind phase.
  • Subjects with chronic pain e.g. musculoskeletal , neuropathic, joint etc.
  • Subjects with chronic pain e.g. musculoskeletal , neuropathic, joint etc.
  • a daily NSAID dose for at least 30 days prior to the study, who required additional relief of their chronic pain, and who completed the screening evaluations were enrolled in the open-label phase on Day 0 and began open- label study medication on Day 1.
  • Tramadol hydrochloride was titrated in 50 mg/day increments to 200 mg/day over four days. Subjects continued on the 200 mg/day dosage for up to an additional 10 days.
  • Subjects were randomized on Day 0 and began double-blind therapy on Day 1 with one of three dosage regimens of tramadol hydrochloride that employed either a 10-, 16- or 13 -day titration schedule in order to achieve a maximum dose of either 200 mg/day for the 10- and 16-day regimen or 150 mg/day for the 13 -day regimen.
  • the subjects took double-blind study medication consisting of either 25 mg of tramadol hydrochloride or matching placebo (two capsules q.i.d.).
  • the three tramadol hydrochloride dosage regimens were designed to achieve a maximum dose (200 mg/day or 150 mg/day) at different rates of titration (10- , 16- or 13-day) .
  • Subjects assigned to the 10 -day titration group received tramadol hydrochloride at 50 mg q.d. on Days 1-3, 50 mg b . i . d . on Days 4-6, 50 mg t.i.d. on Days 7-9 and 50 mg q.i.d. on Days 10-28; subjects assigned to the 16-day titration group received tramadol hydrochloride at 25 mg q.d. on Days 1-3, 25 mg b.i.d. on Days 4-6, 25 mg t.i.d. on Days 7-9, 25 mg q.i.d. on Days 10-12, 50 mg t.i.d. on Days 13-15 and 50 mg q.i.d.
  • Efficacy evaluations were performed at all visits. These evaluations included a subject assessment of pain using a 10 cm pain visual analogue (PVA) scale and overall assessments of the study medication made by the subject and the investigator. Safety evaluations were performed at screening, at the end of the open-label/run-in phase and at the end of the double-blind phase and included assessments of the occurrence of adverse events, vital signs and body weight measurements and physical examinations .
  • PVA pain visual analogue
  • the primary analysis group included 167 subjects, including 54, 59 and 54 subjects in the tramadol hydrochloride treatment groups that employed 10-, 16- and 13-day titration periods, respectively.
  • Chronic low-back syndrome and osteoarthritis were the most common chronic painful conditions reported for the overall population (each represented 28.1% of subjects). The relative proportions of other chronic painful conditions varied somewhat across treatment groups.
  • the mean reduction from baseline PVA scores for subjects in the open-label/run-in phase was 2.1 cm.
  • the mean reduction from baseline PVA scores was highest in the 13 -day tramadol hydrochloride titration group (1.6 cm), followed by the 16-day titration group (1.5 cm); and the 10-day titration group (1.4 cm) .
  • the survival curve plots the relationship between the cumulative probability of discontinuation and the length of exposure. Examination of the curves ( Figure 2) shows the cumulative probability of discontinuation due to nausea and/or vomiting in the three titration groups to be similar through the first five days of titration.
  • the survival curve plots the relationship between the cumulative probability of discontinuation and length of exposure. Examination of the curves ( Figure 3) shows the cumulative probability of discontinuation due to any adverse event in the three titration groups to be similar through the first five days of titration.
  • the cumulative probability of discontinuation due to any adverse event in the 10-day and 16-day titration groups continue to increase while the survival curves of the 13- day titration group begins to fall below them.
  • the survival curves of the 16-day and 13 day titration groups begin to plateau while the cumulative probability of discontinuation in the 10 -day titration group continues to increase.
  • the median time to discontinuation due to any adverse event was shorter for the 16 -day tramadol hydrochloride titration group (6.0 days; Figure 5) followed by the 13- day group (6.5 days) and the 10-day group (9.0 days) .

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  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne un schéma posologique d 'administration de tramadol, pour le traitement de la douleur. Le schéma posologique implique une vitesse d'administration initiale du tramadol inférieure, qui occasionne un pourcentage d'interruptions de la thérapie inférieur du fait que l'incidence et la gravité des effets secondaires sont réduites.
EP99951876A 1998-11-02 1999-10-12 Schema posologique analgesique Withdrawn EP1126834A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US10656798P 1998-11-02 1998-11-02
US106567P 1998-11-02
PCT/US1999/023513 WO2000025769A1 (fr) 1998-11-02 1999-10-12 Schema posologique analgesique

Publications (1)

Publication Number Publication Date
EP1126834A1 true EP1126834A1 (fr) 2001-08-29

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ID=22312128

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99951876A Withdrawn EP1126834A1 (fr) 1998-11-02 1999-10-12 Schema posologique analgesique

Country Status (13)

Country Link
EP (1) EP1126834A1 (fr)
CN (1) CN1346266A (fr)
AR (1) AR021054A1 (fr)
AU (1) AU763273B2 (fr)
BR (1) BR9914981A (fr)
CA (1) CA2348907A1 (fr)
CZ (1) CZ20011535A3 (fr)
EA (1) EA003557B1 (fr)
HR (1) HRP20010311A2 (fr)
HU (1) HUP0104260A3 (fr)
NO (1) NO20012133L (fr)
PL (1) PL348808A1 (fr)
WO (1) WO2000025769A1 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1905435A3 (fr) * 2003-03-11 2008-05-14 Euro-Celtique S.A. Régime de dosage de titrage pour tramadol à libération contrôlée
US7413749B2 (en) * 2003-03-11 2008-08-19 Purdue Pharma L.P. Titration dosing regimen for controlled release tramadol
US20060172006A1 (en) * 2003-10-10 2006-08-03 Vincent Lenaerts Sustained-release tramadol formulations with 24-hour clinical efficacy
CN101252932B (zh) 2005-09-09 2012-10-03 安吉利尼莱博法姆有限责任公司 用于一天给药一次的曲唑酮组合物
CA3015420C (fr) * 2016-02-29 2023-09-26 Grunenthal Gmbh Titrage de cebranopadol

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0025769A1 *

Also Published As

Publication number Publication date
HRP20010311A2 (en) 2002-06-30
AU6422499A (en) 2000-05-22
HUP0104260A2 (en) 2002-08-28
AR021054A1 (es) 2002-06-12
CZ20011535A3 (cs) 2002-08-14
BR9914981A (pt) 2001-10-30
HUP0104260A3 (en) 2002-11-28
EA003557B1 (ru) 2003-06-26
PL348808A1 (en) 2002-06-17
CA2348907A1 (fr) 2000-05-11
NO20012133D0 (no) 2001-04-30
EA200100501A1 (ru) 2001-10-22
AU763273B2 (en) 2003-07-17
WO2000025769A1 (fr) 2000-05-11
CN1346266A (zh) 2002-04-24
NO20012133L (no) 2001-07-02

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